IDH2 deficiency exacerbates cisplatin nephrotoxicity

Abstract

Mitochondrial NADP+-dependent isocitrate dehydrogenase (IDH2) is a major producer of NADPH in the mitochondria and plays a critical role in the redox balance. Cisplatin is an effective anticancer drug, however, its nephrotoxicity, by the breaking of redox balance, limits its use. Here, we investigated whether the cisplatin nephrotoxicity is associated with IDH2. IDH2 gene-deleted (IDH2-/-) and wild type (IDH2+/+) mice were administrated cisplatin with or without Mito-TEMPO, a mitochondria-specific antioxidant. Cisplatin reduced IDH2 activity and expression and NADPH levels in the kidney together with mitochondrial oxidative injury. Mitochondrial damage after cisplatin injection was greater in the IDH2-/-than IDH2+/+ kidneys. These changes were more pronounced in the IDH2-/- than IDH2+/+ kidneys, showing greater renal functional and morphological impairments in the IDH2-/-mouse. Mito-TEMPO reduced those cisplatin-induced kidney injuries both in IDH2-/- and IDH2+/+ mouse. This reduction in the IDH2-/- mouse was more prominent than that in the IDH2+/+ mouse. These results indicate that IDH2 deficiency worsens cisplatin nephrotoxicity by increasing oxidative stress, suggesting that cisplatin-induced nephrotoxicity is associated with mitochondrial IDH2.